Worldwide, 50 million people suffer from epilepsy, and for 25% of these patients the seizures are not controlled by any available medical or surgical treatments. Development of new treatment options and improving the efficacy of epilepsy surgery are presently limited by our poor understanding of how epileptic brain generates spontaneous seizures (ictogenesis). There is accumulating evidence that high-frequency epileptiform oscillations (60 - 500 Hz) are a unique signature of epileptic brain, and play an important role in neocortical seizure ictogenesis [1-3]. As part of a program to develop the principal investigator's (PI) career as a clinician-investigator, we propose a multidisciplinary collaboration between the Mayo Clinic and University of Pennsylvania directed at understanding neocortical ictogenesis and improving the ability to localize regions of epileptogenic brain. This project is an initial step toward a more complete understanding of a common, and difficult to treat, neurological disease. We will develop bioengineering methods to detect and quantify high-frequency epileptiform oscillations (HFEO) from human intracranial EEG recordings. We will investigate the clinical usefulness of HFEO as a signature of epileptogenic brain for epilepsy surgery and seizure prediction. We believe understanding the cellular and network mechanisms underlying HFEO will improve our ability to localize regions of focal epileptogenic brain, an area presently limiting the success of epilepsy surgery, while laying the foundation for the rational development of new therapies such as implantable devices for seizure prediction and prevention. The proposed project will continue a collaboration that combines the neuroscience and neuroengineering strengths of the University of Pennsylvania with the clinical strength of the Mayo Clinic's large surgical epilepsy practice, thus providing a fertile environment for a developing clinician-investigator. The principal investigator has demonstrated potential for independent patient-based research, and with the training provided by this project will develop an independent research program translating advances in neuroengineering and clinical research into clinical practice.